LSS

protein-coding

lanosterol synthase

Gene summary

The protein encoded by this gene catalyzes the conversion of (S)-2,3 oxidosqualene to lanosterol. The encoded protein is a member of the terpene cyclase/mutase family and catalyzes the first step in the biosynthesis of cholesterol, steroid hormones, and vitamin D. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Feb 2009]

MANE transcript

NM_002340.6

Inheritance

AD, AR

ClinVar variants

P:41U:161B:70

Top phenotype

Cataract 44; Alopecia-intellectual disability syndrome 4; Hypotrichosis 14

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr21:46,188,141-46,228,824

External References & Databases

Ensembl (ENSG00000160285)

Transcript & Mutation Effects

hg38 • Region Span ~40.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypotrichosis simplexSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018914

Submitter: Orphanet

cataract 44LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014673

Submitter: Ambry Genetics

cataract 44STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014673

Submitter: Labcorp Genetics (formerly Invitae)

hypotrichosis 14MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032649

Submitter: Ambry Genetics

total early-onset cataractSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0021548

Submitter: Orphanet

alopecia-intellectual disability syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030009

Submitter: Labcorp Genetics (formerly Invitae)

alopecia-intellectual disability syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030009

Submitter: PanelApp Australia

cataract 44STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014673

Submitter: G2P

cataract 44STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014673

Submitter: PanelApp Australia

hypotrichosis 14STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032649

Submitter: PanelApp Australia

autosomal recessive palmoplantar keratoderma and congenital alopeciaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0008923

Submitter: G2P

Clinical Genomic Database (CGD)

Cataract 44; Alopecia-intellectual disability syndrome 4; Hypotrichosis 14AR

Manifestation: Dermatologic; Genitourinary; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Research investigations suggest that lanosterol may be beneficial for prevention and treatment of Cataract 44

Refs: 26200341; 30401459; 30723320

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LSS variants in ClinVar

9 Conditions Cataloged

not providedTotal: 196

Inborn genetic diseasesTotal: 110

Alopecia-intellectual disability syndrome 4Total: 29

LSS-related disorderTotal: 18

Cataract 44Total: 16

Hypotrichosis 14Total: 15

not specifiedTotal: 7

Skin disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002340.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	49 clinvar	2 clinvar	57
missense	10 clinvar	10 clinvar	145 clinvar	15 clinvar	4 clinvar	184
nonsense	5 clinvar	1 clinvar	1 clinvar			7
start loss	2 clinvar		1 clinvar			3
frameshift	3 clinvar	3 clinvar	2 clinvar			8
splice donor/acceptor (+/-2bp)	2 clinvar	5 clinvar	6 clinvar			13
Total	22	19	161	64	6	272

Highest pathogenic variant AF is 0.00013382983

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 50 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002340.6	RefSeq	NP_002331.3	22	MANE Select
ENST00000397728.8	Ensembl	ENSP00000380837.2	22	MANE Select
NM_001001438.3	RefSeq	NP_001001438.1	22	Standard
NM_001145436.2	RefSeq	NP_001138908.1	22	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Steroid biosynthesis - Homo sapiens (human)
Simvastatin Action Pathway
Pravastatin Action Pathway
Atorvastatin Action Pathway
Hyper-IgD syndrome

Biological Process

steroid biosynthetic process
cholesterol biosynthetic process
regulation of protein stability
regulation of cholesterol biosynthetic process

Molecular Function

lanosterol synthase activity

Cellular Component

endoplasmic reticulum membrane
lipid droplet
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000397728
Coding exons: 22
Length: 40684
Individuals with no LoFs: 125677
Homozygous LoFs: 0
Heterozygous LoFs: 71
Defined: 125748
p: 0.000282

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.665	424	464	0.913	0.0000294	4703
Missense (PolyPhen)		145	173.46	0.83591		1819
Synonymous	-0.439	208	200	1.04	0.0000140	1414
Loss of Function	3.77	20	48.2	0.415	0.00000234	499

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00053	0.00049	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00011	0.00011	rare
Finnish	0.00014	0.000092	rare
European (Non-Finnish)	0.00035	0.00034	rare
South Asian	0.00027	0.00020	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the cyclization of (S)-2,3 oxidosqualene to lanosterol, a reaction that forms the sterol nucleus. Through the production of lanosterol may regulate lens protein aggregation and increase transparency. {ECO:0000269|PubMed:26200341, ECO:0000269|PubMed:7639730}.;
Disease: DISEASE: Cataract 44 (CTRCT44) [MIM:616509]: An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. In general, the more posteriorly located and dense an opacity, the greater the impact on visual function. {ECO:0000269|PubMed:26200341}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.386

Intolerance Scores

LoFtool: 0.798
RVIS EVS: 0.54
RVIS percentile EVS: 81.1

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.955

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium